Impact of Target-Mediated Drug Disposition on Linagliptin Pharmacokinetics and DPP-4 Inhibition in Type 2 Diabetic Patients

The pharmacokinetics of the novel dipeptidyl-peptidase 4 (DPP-4) inhibitor linagliptin is nonlinear. Based on in vitro experiments, concentration-dependent binding to DPP-4 is the most likely cause for the nonlinearity. Population pharmacokinetic/pharmacodynamic modeling was performed using linagliptin plasma concentrations and plasma DPP-4 activities from 2 phase 2a studies. In these studies, type 2 diabetic patients received either 1, 2.5, 5, or 10 mg of linagliptin once daily over 12 days (study 1) or 2.5, 5, or 10 mg of linagliptin once daily over 28 days (study 2). The modeling results supported the hypothesis that linagliptin exhibits target-mediated drug disposition. The linagliptin plasma concentrations were best described by a 2-compartment model including concentration-dependent protein binding in the central and peripheral compartment. The plasma DPP-4 activity was included in the model in a semi-mechanistic way by relating it to the model-calculated plasma DPP-4 occupancy with linagliptin. The target binding has a major impact on linagliptin pharmacokinetics. Although unbound linagliptin is cleared efficiently (CL/F 220 L/h), the concentration-dependent binding is responsible for the long terminal half-life (similar to 120 hours) of linagliptin and its nonlinear pharmacokinetics. The model allowed a comprehensive understanding of the impact of target-mediated drug disposition and provides a useful tool to support clinical development.